(1) The trace element vanadium can act like insulin, a major regulator of lipid metabolism. We demonstrated that in vitro, vanadium at concentrations as low as 250 nM significantly reduces synthesis of the major atherogenic protein apolipoprotein B-100 in Caco-2 cells (an intestinal human cell line). In addition, another form of apoB, apoB-48, considered nonatherogenic, is increased by vanadium. Vanadium is known to be a nonspecific phosphatase inhibitor. To further evaluate the molecular mechanism, various specific kinase activators and phosphatase inhibitors are being evaluated.In a pilot in vivo study, a rabbit model of familial hypercholesterolemia (Watanabe breed) with elevated cholesterol, triglycerides and atherosclerosis was fed vanadate. A reduction was seen in cholesterol, triglyceride, and apolipoprotein B as well as an increase in HDL cholesterol, the so called "good cholesterol." A followup study with 10 rabbits as well as rats will be done to further delineate the physiologic effects of vanadium. (2)We have begun a study has begun evaluating the effect of niacin, a lipid lowering drug, on the markedly atherogenic lipoprotein Lp(a) in patients with systemic lupus erythematosus (SLE); another study is evaluating thyroid hormone induced changes in Lp(a) in thyroid cancer patients. During treatment for thyroid cancer, thyroid hormone levels are iatrogenically varied,allowing the effect of high and low levels of thyroid hormone on Lp(a) to be determined. We have begun a trial in these patients to examine the effect of niacin, another lipid lowering drug, on the markedly atherogenic lipoprotein Lp(a). It is known that Lp(a) is an acute phase reactant, a question is what triggers its release.Another collaborative study involves determining if IL-6 may induce Lp(a) release in normal individuals. (3) We are also developing transgenic and knockout REPR mice using a new methodology--RNA/DNA hybrids. With this procedure the RNA targets the hybrid to a specific region in the genome, the DNA portion is then able to undergo homologous recombination inserting the desired change within the genome. The method can now induce a single base change in cultured cells.